Diaryl substituted benzocycloalkanes



United States Patent 3,470,234 DIARYL SUBSTITUTED BENZOCYCLOALKANESWilliam Laszlo Bencze, New Providence, N.J., assignor to CibaCorporation, New York, N.Y., a corporation of Delaware No Drawing.Continuation-impart of application Ser. No.

451,651, Apr. 28, 1965, which is a continuation-inpart of applicationSer. No. 401,256, Oct. 2, 1964. This application Aug. 23, 1965, Ser. No.481,954

Int. Cl. C07c 6'9/76; A61k 27/00 US. Cl. 260473 28 Claims ABSTRACT OFTHE DISCLOSURE Diaryl-benzocycloalkanes of the formula Ph =a phenyleneAl=lower aliphatic radical X=free or functional converted carboxy Ar=anaryl radical and salts thereof, exhibit hypocholesterolemic effects.

This is a continuation-in-part of application Ser. No. 451,651, filedApr. 28, 1965, now abandoned, which in turn is a continuation-in-part ofapplication Ser. No. 401,- 256, filed Oct. 2, 1964, now abandoned.

The present invention concerns and has for its object the provision ofdiaryl-benzocycloalkanes of the Formula I:

in which Ph stands for a 1,2-phenylene radical, the portion -(C H forlower alkylene forming with Ph; 21. fiveto seven-membered ring andcarrying the groups Ar and Ph O-alk-X on two ring-carbon atoms, Ph for aphenylene radical, alk for a lower aliphatic radical, X for a free orfunctionally converted carboxy group and Ar for a carbocyclic orheterocyclic aryl radical, and salts of such compounds havingsalt-forming groups, as well as methods for the preparation of thesecompounds.

The 1,2-phenylene (o-phenylene) radical Ph is unsubstituted orsubstituted by one or more than one of the same or of differentsubstituents attached to any of the four positions available forsubstitution. Such substituents are primarily the following: loweralkyl, e.g., methyl, ethyl, n-propyl or isopropyl, etherified hydroxy,especially lower alkoxy, e.g., methoxy, ethoxy, n-propoxy, isopropoxy orn-butoxy, esterified hydroxy, particularly halogeno, e.g., fluoro,chloro or brorno and trifluoromethyl. Above all, the 1,2-phenyleneradical Ph stands for 1,2- phenylene, (lower alkyl)-1,2-phenylene,(lower alkoxy)- 1,2-phenylene, (halogeno)-l,2-phenylene and(trifluoromethyl)-l,2-phenylene.

The lower alkylene portion --(C,,H substituting two adjacent positionsof Ph may be unbranched or branched and has preferably from three toseven, particularly three to five carbon atoms. Accordingly, the lettern in the above group stands preferably for an integer from 5 to 7. Aboveall, two adjacent ring-carbon atoms thereof, one of which is preferablyadjacent to the 1,2- phenylene radical Ph carry the radicals Ar and Ph-O-alk-X. Said alkylene portion represents, for example, 1,3-propylene,1,3-, 2,4- or 1,4-butylene, 2- or 3-methyl-1,4-butylene,2,3-dimethyl-1,4-butylene, 1,4-, 2,5- or 1,5-pentylene,3-methyl-1,4-pentylene, 2-methyl-1,5- pentylene, 1,4-, 2,5- or1,5-hexylene, 2,6- or 3,5-heptylene.

The phenylene radical Ph preferably contains only one, but may have morethan one of the substituent O-alk-X and/or other substituents in any ofthe positions available for substitution. More particularly, Ph standsfor a 1,4-phenylene radical. Additional substituents are, for example,lower alkyl, lower alkoxy, halogeno and/ or trifluoromethyl, e.g., thosespecifically mentioned for Ph The lower aliphatic radical alk preferablyrepresents lower alkylene, alkenylene or alkynylene, preferably suchhaving from one to five carbon atoms, such as methylene, 1,1- or1,2-ethylene, 1,1-, 1,2-, 2,2- or 1,3-propylene, 1,1-, 1,2-, 2,2-, 1,3-,2,3- or 1,4-butylene, 1,1-, 2,2-, 3,3- or 2,4-pentylene; ethenylene,1,2-, 2,3- or 1,3-propenylene, 1,4-butenylene, 1,4- or 2,3-but-2-enyleneor 2,3-pent-2- enylene; ethynylene, 1,3-pr0pynylene, 1,3-butynylene,1,4- but-Z-ynylene or 1,4-pent-2-ynylene. The radical alk may also standfor a 1,1-cycloalkylidene radical having from three to eight, preferablyfrom five to seven, ring-carbon atoms, e.g., 1,1-cyclopentylidene,1,1-cyclohexylidene or 1,1-cycloheptylidene, as well as1,1-cyclopropylidene, 1,1- cyclobutylidene or 1,1-cyclooctylidene.

The group X preferably stands for free or esterified carboxy, thelatter, for example, contains above all lower alkyl, e.g., methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary butyl ortertiary butyl but also substituted lower alkyl, particularly tertiaryamino-lower alkyl or lower alkoxy-lower alkyl in which the amino oralkoxy group is separated from the carboxy-oxygen by at least two carbonatoms, referably by two or three carbon atoms. A tertiary amino group isabove all N,N-di-lower alkylamino, e.g., dimethylamino or diethylamino,as well as N,N-alkyleneimino, mono-oxaor -aza-alkyleneimino having fromfour to seven ring members, such as pyrrolidino, piperidino, morpholinoor 4-lower alkyl-piperazino, e.g., 4-methyl-piperazino. Lower alkoxy is,for example, methoxy or ethoxy. More particularly X represents carboxy,carbo-lower alkoxy and carboxy esterified by 2- di-lower alkylaminoorlower alkyleneimino-ethyl or 2- lower alkoxy-ethyl. X, however, may alsostand for a carbamyl, monoor di-lower alkyl-carbamyl or nitril group.

A carbocyclic aryl radical Ar, preferably represents monocycliccarbocyclic aryl, i.e., phenyl or phenyl substituted by one or more thanone of the same or of different substituents attached to any of thepositions available for substitution. More particularly Ar stands forphenyl, (lower alkyl)-phenyl, (lower-alkoxy)-phenyl, (halogeno)-phenyl,(trifiuoromethyl)phenyl or X-alk- O-phenyl. A heterocyclic aryl radicalAr is particularly a hexacyclic azacyclic aryl radical, especially apyridyl radical, e.g., 3- or 4-pyridyl.

The compounds of the invention possess valuable pharmacologicalproperties. For example, they cause a reduction of the cholesterol levelin the blood which can be demonstrated at oral doses between about 1 and20 mg./ kg./day, preferably between and mg./kg./day, on rats which areeither on a normal or high cholesterol diet. Furthermore the compoundsof the invention cause an enlargement of the liver due to an increase insize and number of liver cells and a shortening of the duration of thepharmacological effects exhibited by barbiturate compounds. Therefore,they are useful as hypocholesterolemic agents bringing about anamelioration of certain syndromes, such as those caused byarteriosclerosis, e.g., atherosclerosis. Furthermore, they are useful asliver-protecting agents, for example, in the treatment of liverpoisoning caused by chemicals, e.g., carbon tetrachloride and the like,or disease, e.g., liver cirrhosis and the like, as agents limitingbarbiturate-induced sleep and as research tools.

Particularly useful are compounds of the Formula II:

R O-alkr-CCOR:

atom by at least two carbon atoms, R for phenyl, (lower alkyl)-phenyl,(lower alkoxy)-phenyl, (halogeno)-phenyl and (R OOC-alk -O)-phenyl andthe letter mstands for one of the integers 1,2-and 3, and salts of thecompounds having salt-fonming groups.

Outstandingly valuable compounds are those of the Formula III:

in which R, more especially stands for hydrogen, but also for loweralkyl, lower alkoxy or halogeno, each of R and R for hydrogen or methyl,R for hydrogen or lower alkyl and R for phenyl or (halogeno)-phenyl, andalkali metal salts of the compounds in which R, stands for hydrogen.

In the above compounds the two aromatic groups substituting thealiphatic portion of the bicyclic ring system may have the cis-or thetrans-configuration.

The compounds of the invention are prepared according to methods knownper se. For example, they can be obtained by (a) Converting in acomponnd of the Formula IV:

P in

Ar iv in which Ph, is a phenyl group substituted at least by one Y,which is a substituent capable of being converted into the group--O-alk-X, the substituent Y into said group, or

(b) Replacing in a compound of the Formula V:

Ph CnHIn-I h l nHIn-l Ar (VI) the double bond in the alkenylene portion(C H or (d) Reacting a compound of the Formula VII:

mi LJK or a reactive ester or the unsaturated anhydro derivativethereof, with a compound of the formula in the presence of a Lewis acidand, if desired, converting in a resulting compound having a freecarboxyl group, such group into a functionally converted carboxyl group,and/ or converting in a resulting compound having a functionallyconverted carboxyl group, such grou into a free carboxyl group or intoanother functionally converted carboxyl group, and/or converting aresulting compound having a salt-forming substituent into a saltthereof, and/ or converting a salt of a resulting compound into the freecompound or into another salt and/or separating a resulting mixture ofisomers into the single isomers.

In the starting material of the Formula IV the group Ph, may have one ormore than one substituent Y, which is converted into the group --O-alk-Xin one step or in stages. A particularly suitable substituent Y is ahydroxy group. Its conversion into the desired final group is carriedout according to known methods. For example, the starting materialhaving such phenolic hydroxyl group may be converted into a salt,particularly a metal salt, such as an alkali metal salt, e.g., lithium,sodium or potassium salt. Its formation may be achieved, for example, byreacting the starting material with a metal saltforming reagent, such asan alkali metal hydride or amide, e.g., lithium or sodium hydride,sodium or potassium amide, an alkali metal lower alkoxide, e.g.,lithium, sodium or potassium methoxide, ethoxide or tertiary butoxide,an alkali metal compound of a hydrocarbon e.g., butyl lithium, phenyllithium or phenyl sodium, a metal hydroxide or carbonate, e.g., lithium,sodium or potassium hydroxide, carbonate or hydrogen carbonate orcalcium hydroxide. The preparation of the metal compounds isadvantageously carried out in the presence of a solvent selected on thebasis of the physico-chemical characteristics, e.g., the solubility, ofthe starting material, as well as the reactivity of the metalcompound-forming reagent; suitable solvents are, for example,hydrocarbons, e.g., hexane, benzene, toluene or xylene, ethers, e.g.,diethyl ether, p-dioxane, tetrahydrofuran or diethyleneglycoldimethylether, formamides, e.g., dimethylformamide, lower alkanols,e.g., methanol or ethanol, ketones, e.g., acetone, or solvent mixtures.

The starting material, particularly a salt thereof, is then reacted witha iompound of the formula Rg-Zllk-X in which R stands for a reactiveesterified hydroxyl group. The latter is above all a hydroxyl groupesterified with a strong mineral acid, particularly a hydrohalic acid,e.g., hydrochloric or hydrobromic acid, sulfuric acid or a sulfonicacid, such as a lower alkane sulfonic acid, e.g., methane or ethanesulfonic acid, or a mono-cyclic carbocyclic aryl-sulfonic acid, e.g.,p-toluene sulfonic acid. The preferred reactive esters used as thereagents in the reaction (a) are those of the formula Hal-alk-X in whichHal is halogeno, having preferably an atomic weight greater than 19, andrepresenting above all chloro or bromo.

The reaction of the starting material, particularly a metal compoundthereof, with the reactive ester reagent is preferably carried out in asuitable diluent, for example, the solvent used for the preparation ofthe salt, which, however, may be replaced by or diluted with anothersolvent. If necessary, it is performed while cooling or at an elevatedtemperature, and/or, in the atmosphere of an inert gas, e.g. nitrogen.

The formation of the metal salt of the starting material may also becarried out in situ, i.e., the starting material having a phenolichydroxyl group and the reagent having a reactive esterified hydroxylgroup are reacted together in the presence of a salt-forming reagent, orof another suitable base.

The conversion of a free hydroxyl group substituting Ph in the abovestarting material into the group O-alk-X may also be carried out byreacting the starting material with a compound of the fomula HO-alk-X inthe presence of a condensing agent, such as a di-substituted carbonate,for example, a diaryl carbonate, e.g., diphenyl carbonate or especiallya di-lower alkyl carbonate, e.g., dimethyl or diethyl carbonate, or acarbodiimide, e.g., dicyclohexyl-carbodiimide. The reaction with thecarbonate is advantageously carried out at an elevated temperature,ranging from about 100 to about 210, preferably from about 180 to about200, if desired, in the presence of a transesterification catalyst, suchas sodium or potassium carbonate or a sodium lower alkanoate e.g.,sodium methylate, and preferably in the absence of a diluent.

A further modification of the conversion of a hydroxyl groupsubstituting Ph into the group -O-alk-X, comprises reacting the startingmaterial or a salt thereof with corresponding aliphatic aldehyde orketone in the presence of a trior tetra-halogenated methane derivativeand a strong base.

A trior tetra-halogenated methane derivative used in the above reactionis, for example, chloroform, 1,1,1-trichloro-acetone, bromoform,1,1,1-tribromo-acetone, iodoform, chloral, chloral hydrate, bromal,bromal hydrate, carbon tetrachloride or carbon tetrabromide. A strongbase used in the above procedure is particularly an alkali metalhydroxide, e.g., sodium or potassium hydroxide, which is preferably usedin solid form. The reaction is advantageously carried out in thepresence of a diluent, which may be furnished by an excess of the ketonereagent, and at an elevated temperature, it necessary, in a closedvessel and/or, in the atmosphere of an inert gas, e.g., nitrogen.

A further substituent Y capable of being converted into the radicalO-alk-X is the group OCOR in which R stands for halogeno, particularlychloro or bromo, or etherified hydroxy, primarily lower alkoxy, e.g.methoxy or ethoxy, as well as phenoxy.

A starting material having such substituent is reacted with a compoundof the formula HO-alk-X and the reaction is carried out according toknown methods, preferably at temperatures ranging from about 100 toabout 210, if desired, in the presence of a suitable transesterificationcatalyst, e.g., sodium or potassium carbonate and in the absence orpresence of a suitable diluent.

In the starting material of Formula V, Z is primarily hydroxy, but mayalso be esterified hydroxy, particularly halogeno, e.g., chloro orbromo. It preferably substitutes the same carbon atom as the group PhO-alk-X.

The group Z may be replaced by hydrogen according to known eliminationmethods, for example, by treating the starting material with hydrogen,e.g., hydrogen in the presence of a catalyst, e.g., a palladium catalystor Raney nickel and a suitable diluent, e.g., ethanol, or nascenthydrogen, generated, for example, by the action of metals on acids,e.g., zinc and acetic acid, if necessary at an increased pressure and/orat an elevated temperature.

Starting materials of the Formula VI may be converted into the compoundsof the invention according to known methods, preferably by treatmentwith catalytically activated hydrogen, using, for example, a catalystcontaining a metal of the eighth group of the Periodic System, such as apalladium catalyst, e.g., palladium on charcoal, and a solvent, e.g.,ethyl acetate or ethanol, or a solvent mixture, if necessary, at anelevated temperature, and/or under pressure. According to thisprocedure, the cis-epimers of the compounds having the Formula I arepredominantly formed, i.e., those in which the Ar and Ph -O-alk-X moietyhave the same spatial orientation.

In the starting material of the Formula VII the hydroxyl groupsubstituting a ring-carbon atom of the alkylene radical is preferablylocated at the 1-position, i.e., adjacent to the 1,-2-phenylene radical.Accordingly, the double bond of the anhydro derivative thereof is inconjugation with Ph The reaction is carried out according to knownmethods, for example, by reacting the two components in the presence ofa Lewis acid, such as a strong inorganic acid, e.g., sulfuric orphosphoric acid, or a Friedel-Crafts reagent, e.g., aluminum chloride orferric chloride.

In a resulting compound with a free carboxyl group, such group isconverted into a functionally converted carboxyl group according toknown procedures. For example, a free carboxyl group is converted intoan esterified carboxyl group, for example, by treatment of thecarboxylic acid compound with an alcohol, such' as a lower alkanol, inthe presence of an esterifying acidic reagent, e.g., hydrochloric orsulfuric acid, or with a diazocompound, e.g., a lower diazo-alkane, orby converting the carboxylic acid compound into a carboxylic acidhalide, e.g., chloride, and reacting the latter with an alkali metal,e.g., sodium or potassium, alcoholate, e.g., lower alkanolate, or byreacting a salt of the carboxylic acid compound with a reactive ester ofan alcohol, such as an aliphatic halide, e.g., a lower alkyl halide, aswell as an N,Nxlisubstituted amino-lower alkyl halide or an acidaddition salt thereof, in the presence of a metal saltforming base,e.g., potassium carbonate, or any other suitable esterificationprocedure.

A free carboxyl group in a resulting compound may also be converted intoa functionally converted carboxyl group other than an esterifiedcarboxyl group, such as a nitrogen-containing functionally convertedcarboxyl group. For example, a carboxylic acid halide derivative may bereacted with ammonia, a primary or a secondary amine to yield .acarboxamide compound, or the ammonium salt of a carboxylic acid compoundmay be dehydrated, for example, by treatment with a suitable dehydratingreagent, e.g., phosphorus pentoxide or phosphorus oxychloride, to yieldthe corresponding amide; the latter may be further dehydrated to yieldthe corresponding nitrile compound.

A functionally converted carboxyl group in a resulting compound may beconverted into a free carboxyl group. For example, an esterifiedcarboxyl group may be converted into a free carboxyl group byhydrolysis, for example, by treatment with a base, e.g., sodium orpotassium hydroxide, or any other suitable hydrolysis reagent. Or, thecyano group or a carboxamide group in a resulting compound may beconverted into the free carboxyl group by hydrolysis with a strong base,e.g., sodium or potassium hydroxide, or a strong acid, e.g., sulfuricacid.

A functionally converted carboxyl group in a resulting compound may beconverted into another functionally converted carboxyl group. Forexample, an esterified carboxyl group may be converted into anotheresterified carboxyl group by transesterification, for example, bytreatment with an alcohol, e.g., a lower alkanol, in the presence of atransesterification reagent, for example, a metal alcoholate, such as analkali metal, e.g., sodium or potassium, lower alkoxide, or an aluminumlower alkoxide, an alkali metal cyanide, e.g., potassium cyanide, orbenzyl trimethyl ammonium hydroxide. An esterified carboxyl group may beconverted into a carboxamido group, for example, by treatment withammonia, a primary or secondary amine, if necessary, under increasedpressure.

Furthermore, a cyano group in a resulting compound may be converted intoan esterified carboxyl group, e.g., the carbo-lower alkoxy group, forexample, by treatment of the nitrile compound with an alcohol, e.g., alower alkanol, in the presence of a suitable mineral acid, e.g.,sulfuric or hydrochloric acid.

A resulting compound having a free carboxyl group may be converted intoits salts according to conventional methods, for example, by reactingthe compound having a free carboxylic group with an about stoichiometricamount of a suitable salt-forming reagent, such as ammonium hydroxide,or an alkali metal hydroxide, amide or hydride, in the presence of adiluent and evaporating the latter. A salt of this type may bereconverted into the free carboxylic acid compound by treatment with anacid, e.g., hydrochloric, sulfuric or acetic acid.

A resulting compound having an acid addition saltforming group, such asan amino group, may be converted into an acid addition salt thereof, forexample, by reacting a solution of such compound in a solvent or solventmixture, with an acid, such as one of the acids mentioned below or witha suitable anion exchange preparation, and isolating the desired salt.The latter may be converted into the free base by treatment with a basicreagent, e.g., a metal hydroxide, ammonia or a hydroxyl ion exchangepreparation.

Resulting mixtures of isomers may be separated into the single isomers.For example, mixtures of cisand trans-isomers may be separated into thesingle isomers by exploiting the physico-chemical differences, such asdifferences in solubility or different boiling points of such compounds.Racemates are resolved into antipodes according to conventionalresolution procedures, for example, by using the racemate of a freecarboxylic acid compound, forming a salt thereof with an opticallyactive base, e.g., brucine, quinine or strychnine, separating theresulting salt mixture into the single salts and converting the isolatedsalt into the free, optically active carboxylic acid compound bytreatment with a suitable acid.

Accordingly, the compounds of the invention are obtained in the freeform or in the form of their salts, depending on the conditions underwhich the process is carried out. In view of the close relationshipbetween the free compounds and the compounds in the form of their salts,whenever a free compound is referred to in this context, a correspondingsalt, especially a pharmaceutically acceptable salt, is also intended,provided such is possible or appropriate under the circumstances.

Whenever the salt forming group in the compounds of the invention is acarboxyl group, salts are, for example, ammonium or, more particularly,metal salts, such as salts with alkali metals, e.g., sodium orpotassium, or with alkaline earth metals, e.g., magnesium or calcium.Compounds, in which such group is a basic esterified carboxyl group,form acid addition salts, for example, those with inorganic acids, e.g.,hydrochloric, hydrobromic, sulfuric, or phosphoric acid, or organicacids, such as carboxylic or sulfonic acids, e.g., formic, acetic,propionic, pivalic, glycolic, lactic, malonic, succinic, maleic,hydroxymaleic, malic, tartaric, citric, glucuronic, benzoic,

salicylic, 4-amino-salicylic, 2-phenoxybenz0ic, 2-acetoxybenzoic,nicotinic, isonicotinic, methane sul'fonic, ethane sulfonic, ethane1,2-disulfonic, 2-hydroxyethane sulfonic, p-toluene sulfonic ornaphthalene 2-sulfonic acid. Salts, either those with metals or withacids, may also be used as intermediates, for example, in thepreparation of pharmaceutically acceptable salts, or in the purificationof the free compounds, as well as for identification or characterizationpurposes. Acid addition salts, which are prepared primarily for thelatter, are, for example, those with certain inorganic acids, e.g.,perchloric, phosphotungstic, phosphomolybdic, chloroplatinic or Reineckeacid or with acidic organic nitro compounds, e.g., picric, picrolonic orflavianic acid.

The starting materials of the Formulae IV, V and VII are known or, ifnew, may be prepared according to known methods. Those of the Formula IVmay be prepared analogous to procedure (a) or by reaction of a compoundof the Formula VII, or a reactive ester or the unsaturated anhydroderivative thereof, with a compound of the formula H-Ph in which Ph; isprimarily a phenyl group substituted by hydroxy or a group capable ofbeing converted into hydroxy. The latter is above all an etherifiedhydroxyl group, such as lower alkoxy, e.g., methoxy or ethoxy, as wellas phenyllower alkoxy, e.g., benzyloxy. If necessary, such group isconverted into hydroxyl according to known methods, for example, by acidhydrolysis, e.g., treatment with hydrobromic acid, hydriodic acid orpyridine hydrochloride, by hydrogenolysis, e. g., treatment withcatalytically activated hydrogen, or any other appropriate method. Ifdesired, a hydroxyl group in a resulting starting material is convertedinto a group -OCO-R according to known procedures suitable for theesterification of a phenolic hydroxyl group.

The starting material of the Formula V is prepared by reacting a ketoneof the formula MAI with the Grignard reagent HalMg-Ph -O-alk-X, in whichHal stands particularly for bromo, and carefully decomposing theresulting complex so as not to cause elimination of the hydroxyl groupby dehydration. The intermediates used in the above Grignard reactionare known or may be prepared according to known methods; the Grignardreagent may be prepared, for example, according to the Method ofEntrainment, described by Kharash and Reinmuth, Grignard Reactions ofNonmetallic Substances (Prentice Hall, 1954). In a resulting startingmaterial, the hydroxyl group may be esterified according to knownmethods. Some of the starting materials mentioned are also described inthe co-pending application Ser. No. 411,632, filed Nov. 16, 1964.

The starting material of the Formula VI as well as salts of suchcompounds having salt-forming groups, is new and is intended to beincluded within the scope of the invention; apart from serving as anintermediate, it exerts the above-described hypo-cholesterolemic andliverenlarging effect and is, therefore, used accordingly. Especiallyuseful are the compounds that correspond to those of the Formulae II andHI. They are prepared analogous to procedure (a) or by eliminating thecompound ZH from the starting material of the Formula V. If Z representshydroxy the elements of water are eliminated, for example, by treatmentof the intermediate with an acid, e.g., hydrochloric, sulfuric orphosphoric acid. In the case of Z being an esterified hydroxyl group,the elements of an acid representing H-Z are eliminated by treatmentwith a base, e.g., sodium hydroxide.

The invention also comprises any modification of the process, wherein acompound resulting as an intermediate at any stage of the process isused as starting material, and the remaining step(s) of the process is(are) carried out or the process is discontinued at any stage thereof,or in which the starting materials are formed under the reactionconditions, or in which the reaction components are used in the form oftheir salts.

In the process of this invention, those starting materials arepreferably used, which lead to final products indicated before as beingthe preferred embodiments of the invention.

The new compounds of this invention are useful in the form ofcompositions for enteral or parenteral use, which contain the newcompounds in admixture with a pharmaceutically acceptable solid orliquid carrier. For making up the preparations there are employedcarrier materials, such as water, gelatine, sugars, e.g., lactose,glucose or sucrose, starches, e.g., corn starches, wheat starch or ricestarch, stearic acid or salts thereof, e.g., magnesium or calciumstearate, talc, vegetable oils, stearyl alcohol, benzyl alcohols,tragacanth, gums, acacia, propylene glycol, polyalkylene glycols or anyother known carrier materials used for such compositions. The latter arein solid form, for example, as capsules, tablets or dragees, or inliquid form, for example, as solutions, suspensions or emulsions. Ifdesired, they may contain auxiliary substances, such as preserving,stabilizing, wetting, emulsifying, coloring or flavoring agents, saltsfor varying the osmotic pressure or buffers. The compositions areprepared according to standard methods used in the art of manufacturingsuch compositions, and may also contain, in combination, othertherapeutically useful substances.

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees centigrade.

Example 1 A mixture of 6.74 g. of 1-(4-hydroxy-phenyl)-2-phenyl-1,2,3,4-tetrahydro-naphthalene (containing diethyl ether ofcrystallization) and 0.46 g. of metallic sodium in 100 ml. of xylene isrefluxed for three hours. The suspension is allowed to cool to roomtemperature and is then treated with 4.2 g. of ethyl'Z-bromo-isobutyrate in ml. of xylene. The reaction mixture is refluxedwhile stirring for six hours and is then cooled to room temperature andtreated with 2 ml. of ethanol. The inorganic precipitate is filteredoff, the filtrate is evaporated to dryness. The residue is taken up indiethyl ether; the organic solution is washed with water and a saturatedsodium chloride solution, dried over sodium sulfate and evaporated todryness to yield 11.6 g. of the oily ethyl 2-[4-(2-phenyl-1,2,3,4-tetrahydro-l naphthyl) phenyloxy] isobutyrate of the formula:

which is purified by chromatography on 340* g. of aluminum oxide(neutral, activity III). The desired product is eluted as a colorlessoil with a 9: l-mixture of hexane and benzene, a 4: l-mixture of hexaneand benzene and a 1:1- mixture of hexane and benzene, and crystallizesspontaneously. It melts at 8384 after recrystallization from a mixtureof diethyl ether and petroleum ether.

The starting material used in the above procedure is prepared asfollows: A mixture of 44.8 g. of 2-phenyl-1,2,3,4-tetrahydro-naphthalene-l-ol and 18.8 g. of phenol in ml. of alzl-mixture of benzene and hexane is treated dropwise over a period oftwo hours with a solution of 13.3 g. of aluminum chloride in 37.6 g. ofphenol While stirring and cooling in an ice-bath to 5-10. The ice-bathis then removed and stirring is continued at room temperature for twelvehours; after standing for sixty hours, the reaction mixture is againstirred for four hours at about 38-40", and is then poured onto amixture of 100 g. of ice and 100 ml. of concentrated hydrochloric acid.A total of 50 ml. of diethyl ether is added; the organic layer isseparated, and the aqueous mixture is extracted with two additionalportions of diethyl ether. The combined ether extracts are washed twicewith aqueous solutions of sodium acetate, dried over sodium sulfate,filtered and evaporated to dryness. The excess of phenol is removed bydistillation (collected at 75 13 mm. and a bath temperature of to leave66.5 g. of a glassy residue.

The latter is dissolved in the same amount of diethyl ether and pouredslowly into 500ml. of a 10 percent aqueous solution of sodium hydroxidewhile stirring and keeping it at 50. The diethyl ether evaporates, andthe precipitate is filtered off to yield 66.0 g. of the sodium salt of1-(4-hydroxy-phenyl)-2-phenyl-1,2,3,4-tetrahydro naphthalene, which issuspended in water acidified with 2 N hydrochloric acid. The organicmaterial is extracted with three portions of diethyl ether; the organicsolutions are combined, washed with water, an aqueous solution of sodiumacetate, and an aqueous solution of sodium chloride, dried over sodiumsulfate, and evaporated to dryness, yield: 51.0 g. The resulting1-(4-hydroxy-phenyl)-2- phenyl-l,2,3,4-tetrahydronaphthalene iscrystallized from 100 ml. of hexane and about 2 ml. of diethyl ether. Afirst crop (yield: 20.5 g.) melts at 68-71", and the second crop (yield:9.2 g.) melts at 66-70; a total of 17.3 g. of a glassy residue can beobtained from the mother liquors.

The crystalline material has one-half mole of diethyl ether ofcrystallization, which is eliminated by distillation and collecting thel-(4-hydroxy-phenyl)-2-phenyl-1,2,3,4- tetrahydronaphthalene at 186-190/0.1 mm.

. Example 2 A mixture of 10.4 g. of ethyl 2-[4-( 2-phenyl-1,2,3,4-tetrahydro-l-naphthyl)-phenoxy]-isobutyrate and 50 ml. of methanol isadded to a solution of 1.7 g. of potassium hydroxide in 30 ml. ofmethanol, and the reaction mixture is allowed to stand at roomtemperature for sixty hours. The solvent is then evaporated underreduced pressure. The residue is dissolved in water; the aqueoussolution is washed with diethyl ether and is then acidified with 15 ml.of 2 N hydrochloric acid. The organic material is extracted with diethylether; the organic extracts are combined and washed with a saturatedaqueous solution of sodium chloride, dried over sodium sulfate andevaporated to dryness to yield the2-[4-(2-phenyl-1,2,3,4-tetrahydrol-naphthyl)-phenoxy]-isobutyric acid ofthe formula 11 Example 3 The following compounds are prepared accordingto the previously described and illustrated procedure by selecting theappropriate starting materials:

12 filtered and evaporated to dryness. The residue is crystallized fromdiethyl ether-hexane, thereupon from ethylacetate-petroleum ether andfinally from ethanol-water to yield the trans-{4-[2-(4-chl0rophenyl)1,2,3,4 tetra- StartingMaterial Reagents1(4hydroxy-phenyl)-2-phenyl-1,2,3,4-tetrahydro- Sodium hydride plusmethyl 2-bromo Product Methyl2-[4-(2-phenyl-1,2,3,4'tetrahydro-1-naphthyl)- naphthalene. isobutyrate.phenyloxy1-isobutyrate. 2-(4-chloro-phenyD-1-(4-hydroxy-phenyD-1,2,3,4-Sodium hydride plus ethyl 2 bromo- Ethyl2-(4-[2-(4-chloro-phenyl)-1,2,3,4-tetrahydro-1 tetrahydrdnaphthaIene.isobutyrate: naphthyH-phenyloxy)-isobutyrate.1-(3-ch1oro-4-hydroxyphenyl)-2'pheny11,2,3,4-tetra- .do Ethyl2-[2chloro+(2-phenyl-1,2,3,4-tetrahydro-1- hydro-naphthalene.naphthyl)-phenyloxy]-isobutyrate.1-(4-hydroxy-phenyl)-7-methy1-2-(4-methyl-phenyl)- do Ethyl2-(4-[7-methyl-2-(4-methyl-phenyD-l3,3,4-

1,2,3,4-tetrahydro-naphthalene.tetrahydro-l-naphthyH-phenyloxy)-isobutyrate.7-chloro-1-(4-hydroxyphenyl)-2-phenyl-1,2,3,4-tetra- .do Ethyl2-[4-(7-chloro-2-phenyl-1,2,3,4-tetrahydro-1- hydro-naphthalene. Anaphthyl)-phenyloxy]-isobutyrate.1-(4-hydroxy-Ii-methylphcnyl)-2-phcnyl-1,2,3,4-tetra- Sodium hydrideplus ethyl 2-bromo-2- Ethyl2-[2-methyl-4-(2-phenyl-1,2,3,4-tetrahydro-1- hydro-naphthalene.methyl-butyrate. naphthyl)-phenyloxy]-butyrate.1-(4-hydroxy-pl1enyl)-2-phenyl-1,2,3,4-tetrahydro- Sodium hydride plusethyl l-bromo- Ethyl 1-[4-(2-phenyl-1,2,3,4-tetrahydro-l-naphthyD-naphthalene. eyclohexane carboxylate. phenyloxy1-cyclohexanecarboxylate.

1-(thydroxy-phenyl)-2-phenyl-indane Sodium hydride plus ethyl2-bromoisobutyrate. u yrate.1-(4-hydroxy-phenyl)-2-phenyl-1-benzsuberane. .do Ethyl;271B(i-phenyl-l-benzsuberyl)-phenyloxy]- no 11 yrs. e.2-(thydroxy-phenyl)-1-pl1eny1-1,2,3,4-tetrahydrodo Ethyl2-[4-(1-phenyl-1,2,3,4-tetrahydro-2-naphthyl)- naphthalene.phenyloxy]-isobutyrate.1-(3,4-dihydroxy-phenyl)-2-phenyl-l,2,3,4-tetrahydro ..do1-[3,4-di-(2-carbethoxy-2-propyloxy)-phenyl]-2- naphthalene.phenyl-l,2,8,4-tetrahydro-naphthalene.1-(4-hydroxy-pheny1)-2-(3-pyr1dyD-1,2,3,4-tetra- ..--.do Ethyl2-(4-[2-(3-pyridy1)-1,2,3,4-tetrahydrohydro-naphthalene.naphthylJ-phenyloxy)-isobutyrate. Ethyl2(4-[2-(4-chloro-phenyD-1,2,3,4-tetrahydro-l- Potassium hydroxide inethanol 2-(4-[2-(4-chlorophenyl)-l,2,3,4-tetrahydro-1- naphthyll-phenyly)-1sobutyrate. naphthyl1-phenyloxy)-isobutyric acid. Ethyl2-[2-ehloro-4-(2-pheny1-1,2,3,4-tetrahydro-1- d02-[2-chloro-4-(2-phenyl-l,2,3,4-tetrahydr0-1-naphthyl)-phenyloxy]-1sobutyrate. naphthyl)-phenyloxy]-isobutyric acid.Ethyl 2-[2-methy14-(Z-phenyI-I,2,3,4-tetrahydr0-1- ..do2-[2-methyl-4-(Z-phenyl-l,2,3,4-tetrahydr0-lnaphthyl)-phenyloxy]-isobutyrate.

Ethyl 2-(4-[7-methyl-2-(4-methyl-phenyl)-l,2,3,4-

tetrahydro-l-naphthyH-phenyloxy)-1sobutyrate.

Ethyl 2-[4' (7-ch1oro-2-phenyl-1,2,3,4-tetrahydro-1-naphthyl)-phenyloxy1-isobutyrate.

Ethyl l-[4-(2-phenyl-l,2,3,4tetrahydro-1-naphthy1)-phenyloxylcyclohexane carboxylate.

Ethyl 2-[4-(Z-phenyl-l-indanyl)-phenyloxy]-1sobutyrate. Ethyl2-[4-(2-phenyl-l-benzsuberyl)-pheny1oxy]- isobutyrate. Ethyl2-[4-(l-phenyl-l,2,3,4-tetrahydro-2-naphthyl)- phenyloxy1-isobutyrate.1-[3,4-di-(Z-carbethoxy-2-propyl0xy)-phenyl]-2-phenyl-l,2,3,4-tetrahyfire-naphthalene.2-[4-(2-phenyl1,2,3,Metrahydro-lnapththyl)- phenyloxyl-isobutyric acid.

Potassium hydroxide in methanol Potassium hydroxide in ethanol Potassiumhydroxide in methanol Potassium hydroxide in ethanol Potassium hydroxidein methanol 2-N,N-diethylaminoethyl chloride hydrochloride pluspotassium carnaphthyl)-phenyloxy] isobutyric acid.2-(4-[7-n1ethyl2-(4-methyl-phenyl)-1,2,3,4tetrahydro-l-naphthyl]-phenyloxy)-isobutyricacid. 2-[4- (7-chloro-2'pheny1-l,2,3,4-tetrahydro-lnaphthyl)-phenyloxy]-isobutyric acid.1-[4'(2-phenyl-1,2,3,4-tetrahydro-l-naphthyl)- phenyloxyj-cyclohexanecarboxylic acid. 2-[4-(2-phenyl-1-indanyl)-phenyloxy]-isobutyric ac2-[4-gg-phenyl-l-benzsuberyl)-phenyloxy1-isobutyric 1 2-[4(l-phenyl-l,2,3,4tetrahydro-2-naphthyl)- pheny1oxy]-isobuty'ric acid.1-[3-4-di-(2-caIboxy-?propyloxy)-phenyl]-2-phenyl-1,2,3,4-tetrahydro-naphthaleue. 2-N,N-diethylaminoethyl 2-[4-(2-phenyl-l2,3,4-

tetrahydro-l-naphthy1)-phenyloxy]-isobutyratc.

bonate.

Do 2(l-pi1 r in0)- hy1chloride hYdI0- -(l-piperidinoyethyl2-[4-(2-phenyl-l,2,3,4-tetrachloride plus potassium carbonate.hydro-1-naphtyl)-pheny1oxy]-isobutyrate.

D0 2-methoxyethano1 plus sulfuric acid"... Z-rnethoxyethyl2[4-(2-phenyl-1,2,3,4-tetrahydro-l- Example 4 33.5 g. oftrans-1-(4-hydroxy-phenyl) 2 (4-chlor0-phenyl)-l,2,3,4-tetrahydro-naphthalene are dissolved in 200 ml. ofacetone and the solution is stirred and gently refluxed together with8.0 g. of sodium hydroxide pellets. To this mixture is added dropwise asolution of 10.0 g. of monochloro-acetic acid in 50 ml. of acetone in acourse of 30 minutes during which the reaction mixture becomes a slurry.After completed addition reflux and stirring is continued for 1 morehour and the reaction mixture is allowed to stand for 20 hours.Thereupon reflux and stirring is returned for 1 hour and thereafter theacetone is removed under reduced pressure. The solid residue isdissolved in 1 liter of water and extracted two times with diethylether. Upon evaporation the extract yields a partly crystalline oil,which is discarded. The clear aqueous layer is acidified withconcentrated hydrochloric acid and extracted two times with diethylether. The combined extracts are washed with Water, saturated sodiumchloride solution, dried over sodium sulfate,

naphthyl)-phenyloxy]-isobutyrate.

hydro-l-naphthyl]-phenoxy}-acetic acid having the formula:

0 and melting at 176177.

Example 5 gentle reflux with stirring. Then 4.5 g. of chloroform areadded dropwise with stirring (20 minutes) and heating and stirring iscontinued for 2 more hours. To the white paste formed 300 ml. of icewater are added and the acetone is removed under reduced pressure. Theclear aqueous solution is acidified with concentrated hydrochloric acidand extracted twice with diethyl ether. The extracts are washed withwater, two times with saturated ammonium chloride solution, dried,filtered and evapo rated to dryness. The glasslike solid, crude productis recrystallized from benzene-petroleum ether to yield thetrans-2-{4-[2-(4-chloro-phenyl) 1,2,3,4tetrahydro-lnaphthyl]-phenoxy}-isobutyric acid of the formula:

melting at 126-128.

Example 6 27.2 g. of trans-1-(4 hydroxyphenyl)-2-(4-chlorophenyl)-1,2,3,4-tetrahydro-naphthalene are dissolvedin 200 ml. of acetone with stirring at room temperature. 18.0 g. ofsodium hydroxide pellets are added to the clear solution. The reactionmixture is stirred and heated at reflux for minutes. External heating isremoved and 12.0 g. of chloroform are added dropwise at a rate tomaintain reflux. A precipitate is formed and after completed addition,heating is resumed and 400 ml. acetone are added to facilitate stirringand refluxing which is continued for 2 more hours (58 C.). The batch isthen cooled iri an ice-salt bath (5) for minutes. The tan precipitate iscollected and washed with acetone. This precipitate is then dissolved in400 ml. water; the solution is made acidic (pH 2) with 25 ml.concentrated hydrochloric acid and extracted with 3x 100 m1. methylenechloride. The combined extracts are washed with l 150 m1. saturatedsodium chloride solution, dried over anhydrous magnesium sulfate andevaporated. The residue is recrystallized from benzene-petroleum etherto yield the trans-2-{4-[2-(4chloro-phenyl)-1,2,3,4-tetrahydro-l-naphthyl] phenoxy} isobutyric acidwhich is identical with that obtained according to Example 5.

Example 7 A mixture of 36.50 g. oftrans-2-{4-[2-(4-chloro-phenyl)-1,2,3,4-tetrahydro-l-naphthyl] phenoxy}isobutyric acid, 100 ml. ethanol and 2.0 ml. concentrated sulfuric acidis refluxed for 4 hours. The dark yellow reaction mixture is thentreated with water and extracted with methylene chloride. The combinedextracts are washed with sodium carbonate solution and stripped todryness leaving an oily product. It is recrystallized from acetonehexaneto give rod-like crystals of the trans-2-{4-[2-(4- 14chloro-phenyl)-l,2,3,4-tetrahydro 1 naphthyl] phenoxy}-isobutyric acidethyl ester having the formula:

and melting at 115116.

Example 8 In the manner described in the previous examples the followingcompounds can be prepared by reacting equivalent amounts of thecorresponding reagents:

1- 3-carboxyethoxy-phenyl -2- (4-methoXy-Pl eny1)1,2,3,4-tetrahydro-naphthalene,

1-(4-carboxymethoxy-3-methyl-phenyl) -2- 3-methy1-phenyl)-6-methoxy-1,2,3 ,4-tetrahydro-naphthalene,

1-(2-carboxymethoxy-4-chloro-phenyl)-2-phenyl-1,2,3,4-

tetrahydro-naphthalene,

1- 4-carb oxymethoxy-phenyl) -2- (4-chloro-phenyl) indane,

1-(4-carboxymethoxy-phenyl) 2- (4-chloro-phenyl) benzo-cycloheptane,

1-(4-carboxymethoxy-phenyl) -2- (4-chloro-pheny1) -7-trifluoromethyl-l,2,3,4-tetrahydro-naphthalene,

1- (4-carboxymethoxy-phenyl) -2- (4-chloro-phenyl) 3,3-dimethyl-indane,

1- (4-carboxymethoxy-phenyl -2- 4-chloro-phenyl) 1,4,5-trimethyl-1,2,3,4-tetrahydro-naphthalene,

1-(4-carboxymethoXy-phenyl) -2- (4-chloro-phenyl) -8-methoxy-1,2,3,4-tetrahydro-naphthalene,

1- [4- l-carboxy-ethoxy) -phenyl] -2- (3-methoXy-phenyl)1,2,3,4-tetrahydro-naphthalene,

1- [4- (4-carboxy-butoxy) -phenyl] -2- (3 -bromo-phenyl)- 6-methyl-1,2,3,4-tetrahydro-naphthalene,

1- (4-carbamylmethoXy-phenyl) -2-pheny1- l ,2,3 ,4-

tetrahydro-naphthalene,

1,2-bis- (4-carbethoxymethoxy-phenyl) -1,2,3,4-tetrahydro-naphthalene,

1- 4-carb oxyvinyloxy-phenyl -2- (2-chol0ro-phenyl)1,2,3,4-tetrahydro-naphthalene,

1- (4-N,N-dimethylcarbamylmethoxy-phenyl) -2-phenyl- -methoxy-indane,

1-( 3-cyanomethyl-phenyl) -2- (4-chloro-phenyl) 1,2,3 ,4-

tetrahydro-naphthalene,

1- (4-carbethoxymethoxy-2-chloro-phenyl -2- (4-methoxyphenyl) l ,2, 3,4-tetrahydro-naphthalene and 1- (3-carboxymethoxy-S-methoxy-phenyl) -2(3,4,5-trimethoxy-phenyl) -6,7-dimethoxy 1,2,3 ,4-tetrahydronaphthaleneand the sodium salts of the acids above.

Example 9 The solution of 5.7 g. 1-(4-hydroxy-phenyl)-2-phenyl-7-chloro-1,2,3,4-tetrahydro-naphthalene in 30 ml. acetone is stirredwith 1.48 g. sodium hydroxide pellets and refluxed while a solution of2.41 g. chloro-acetic acid in 30 ml. acetone is added dropwise over a 10minute period and refluxing is continued for 2 /2 hours. The reactionmixture is evaporated to dryness in vacuo, to the residue dilutedhydrochloric acid is added and the whole is extracted with diethylether. The extracts are washed several times with water, then withconcentrated sodium-chloride solution, dried and evaporated. The brownoil crystallizes slowly in hexane-benzene (5:1) while stirring, to yielda first crop melting at 99-113". After two recrystallizations frombenzene-pentane the 4-(2-phenyl-7-chloro-1,2,3,4-tetrahydro-l-naphthyl)-phenoxy-acetic acid of the formula is obtained.Its melting point of 120-123 indicates that it is unitary and mostlikely has the trans-configuration.

The starting material is prepared as follows:

To the cooled and stirred solution of 17.0 g. Z-phenyl-7-chloro-tetralone in 41 ml. ethanol and 41 ml. tetrahydrofuran 1.62 g.sodium boron hydride are added. Stirring is continued at roomtemperature for 5 hours and hereupon the mixture is allowed to standovernight. The excess hydride is decomposed with dilute acetic acid andthe mixture is evaporated under reduced pressure. The residue isslurried in water and the yellow oil is collected; it crystallizes uponstanding. The so-obtained l-hydroxy-2-phenyl-7-chloro-1,2,3,4-tetrahydro-naphthalene is recrystallized oncefrom aqueous ethanol and once from hexane, M.P. 84-86.

13.2 g. thereof and 5.1 g. phenol are dissolved in 147 ml. benzene and49 ml. hexane. This solution is added dropwise to a solution of 10.2 g.phenol and 3.42 g. aluminum chloride while stirring and cooling in icebath. Stirring is continued at room temperature for 5 hours and at 50-55for additional 5 hours. The reaction mixture is poured into 80 g. iceand 80 ml. concentrated hydrochloric acid and the whole is extractedseveral times with diethyl ether. The combined organic layer is washedseveral times with water, concentrated sodium chloride solution, dried,filtered and evaporated in vacuo to dryness.

- The excess phenol is distilled off in the vacuum of a waterjet pumpand the oil, boiling at 183-193/12 mm. collected. It is redistilled andthe fraction boiling at 193- 215 12 mm. collected. The so-obtained1-(4-hydroxyphenyl)-2-phenyl-7-chloro-1,2,3,4-tetrahydro-naphthaleneobviously constitutes a mixture of the cisand trans-ism mer; it is usedas such in the final step.

Example 4.0 g. l-(4-hydroxy-phenyl)-2-(4-chloro-phenyl)-benzosuberaneare dissolved in 20 m1. acetone and the solution is stirred with 1.0 g.sodium hydroxide pellets at gentle reflux. The solution of 1.63 g.chloro-acetic acid in 20 ml. acetone is added dropwise over a 10 minuteperiod. The reaction mixture is refluxed with stirring for 150 minutes,whereupon the sodium salt of the product precipitates as a white solid.It is collected and washed with acetone. The air dried salt is suspendedin water, the suspension acidified with 2 N hydrochloric acid, andextracted 3 times with diethyl ether. The ethereal extracts are washedwith saturated sodium chloride solution, dried, filtered and evaporatedto dryness. The residual solid is recrystallized from 16 benzene-pentaneto yield the 4-[2-(4-chlorophenyl)-1- benzosuberanyl]-phenoxy-aceticacid of the formula melting at 132. NMR-evidence indicates that botharomatic substituents are in equatorial positions (transcompound).

The starting material is prepared as follows:

91 g. p-chlorophenyl-acetonitrile are reacted at room temperature with93 g. 1-chloro-3-phenyl-propane in the presence of 420 ml.dimethylformamide, 420 m1. toluene and 28.8 g. of a 56% suspension ofsodium hydride in mineral oil. The reaction mixture is stirred for 5hours then evaporated under reduced pressure. The residue is slurriedwith water and extracted into diethyl ether. The extract is washed withwater, saturated sodium chloride solution, dried and evaporated. Theresidue is recrystallized from pentane to yield thea-(4-ch1oro-phenyl)-5- phenyl-valeronitrile, M.P. 66-68".

91.6 g. thereof are hydrolyzed by boiling it with 226 g. 50% sodiumhydroxide solution in 340 ml. ethylene glycol for 5 hours. The reactionmixture is poured into 1.5 liters water giving a clear red solution. Itis cooled in an ice bath and acidified with concentrated hydrochloricacid. The supernatant liquid is decanted and pentane added. The whole isfiltered and the filter residue airdried. The so-obtainedm(4-chlorophenyl)-5-phenyl-valeric acid is recrystallized from aqueousethanol and melts at 104-105".

79.5 g. thereof are dissolved in ml. benzene and heated on a steam bathwith 58 g. phosphor pentachloride. The benzene is removed in vacuo and100 ml. benzene are added and again removed. This is repeated 2 timesmore. The remaining acid chloride is taken up in 178 ml. benzene and thesolution added dropwise with stirring to 48.7 g. aluminum chloridesuspended in 445 ml. benzene at room temperature. Stirring is continuedfor 5 hours and the reaction mixture is poured onto ice and concentratedhydrochloric acid. The organic layer is separated and the aqueous layerextracted 2 times with diethyl ether. The combined organic layers arewashed with water and 2 N sodium carbonate solution, dried, filtered andevaporated to dryness. The remaining oil is distilled and the fractionboiling at 240/0.3 mm. collected. It represents the2-(4-chloro-phenyl)-l-benzosuberanone.

8.0 g. thereof in 50 ml. dry ethanol and 20 ml. tetrahydrofuran arereduced at room temperature with 0.8 g. sodium boron hydride. Thereducing agent is added in portions and the reaction mixture is stirredat room temperature for 5 hours. The excess reducing agent is destroyedwith dilute acetic acid and the reaction mixture is evaporated in vacuo.The residue is extracted 3 times with diethyl ether, the extracts washedwith water, dried, filtered and evaporated to dryness. There is obtainedthe 2-(4-chloro-phenyl)-l-benzosuberanol as a straw-colored oil showingin the infrered spectrum a hydroxyl band at 3380 cm.-

To a solution of 1.7 g. aluminum chloride in 5.0 g. phenol is addeddropwise with stirring and cooling in an ice bath a solution of 6.8 g.2-(4-chloro-phenyl)-benzosuberanol and 2.5 g. phenol in 73 ml. benzeneand 24 m1, hexane. After completed addition (60 min.) stirring iscontinued at room temperature for another hours at 5560. The reactionmixture is poured onto 50 g. ice and 50 ml. concentrated hydrochloricacid. The whole is extracted 3 times with diethyl ether. The extractsare washed with water and saturated sodium chloride solution, dried,filtered and evaporated to dryness. The phenol is distilled off at150l70/ 13 mm. and the fraction boiling at 2l5240/ 0.2 mm. collected.There is obtained the desired 1- (4-hydroxy-phenyl -2- (4-chloro-phenyl)-benzosuberane as a glasslike solid.

Example 11 To the stirred solution of 9.6 g. la-(4-hydroxyphenyl)-2a-phenyl-1,2,3,4-tetrahydro-naphthalene and 7.0 g. sodium hydroxidepellets in 100 ml. acetone, 4.5 g. chloroform are added dropwise whilerefluxing, and this is continued for 3 hours after completed addition.The sodium salt formed is collected, washed with acetone, air dried,suspended in water and the suspension acidified with hydrochloric acid.It is extracted with diethyl ether, benzene, ethyl acetate and againwith ether, the combined extracts are washed with saturated sodiumchloride solution, dried and evaporated. The remaining 2-[4-(2ocphenyl1,2,3,4 tetrahydro-la-naphthyl)-phenoxy]-isobutyric acid of the formulais recrystallized from n-hexane and melts at l57159.

The starting material is prepared as follows:

To a mixture of 2.4 g. magnesium turnings in 50 ml. diethyl ether areadded a few drops of methyl iodide to initiate the formation of theGrignard reagent and then a solution of 19.0 g. 4-bromo-anisole in 50ml. diethyl ether. The Grignard mixture is refluxed for two hours and,while cooling with ice, a solution of 6.7 g. 2-phenyl-1,2,3,4-tetrahydro-naphthalene-l-one in 50 ml. of diethyl ether is addeddropwise. After the addition is completed, refluxing is continued foranother 3 hours and the reaction mixture is allowed to stand for 15hours. It is then cooled with ice; the Grignard complex formed is brokenand simultaneously dehydrated by adding 25 m1. of a saturated aqueoussolution of ammonium chloride. The reaction mixture is poured into 200ml. water, the organic solution separated, the aqueous layer extractedtwice with diethyl ether and the organic extracts are combined, Washedwith water, dried and evaporated. The resulting 1(4-methoxy-phenyl)-2-phenyl-3,4-dihydronaphthalene melts at 129-130"after crystallization from benzene-n-pentane.

1.2 g. 10% palladium-charcoal in 100 ml. ethyl acetate are saturatedwith hydrogen at atmospheric pressure. To the suspension the solution of5.4 g. 1-(4-methoxyphenyl)-2-phenyl-3,4-dihydro-naphthalene in 50 ml.ethyl acetate is added and the Whole is allowed to hydrogenate atatmospheric pressure until the hydrogen uptake has stopped. Thereuponthe catalyst is filtered off, the filtrate evaporated under reducedpressure, the residue mixed with water and the mixture extracted withdiethyl ether. The dried extract is evaporated and the viscous oilobtained recrystallized from 2-propanol to yield pure 10(- 18 (4methoxyphenyl)Jot-phenyl-1,2,3,4-tetrahydro-naphthalene melting at87-89.

A solution of 10 ml. pyridine in 12 ml. concentrated hydrochloric acidis distilled until the vapors reach a temperature of about 200. 1.0 g.1u-(4-methoXyphenyl) -2u-phenyl-1,2,3,4-tetrahydro-naphthalene is addedto the melt obtained and the mixture is refluxed for one hour at a bathtemperature of 250. The cooled reaction mixture is diluted with water,the aqueous phase decanted, the residue taken up in benzene, the organicphase is separated, washed with water, dried and evaporated. Theso-obtained 1a-(4-hydroxy-phenyl)-2rx-phenyl-1,2,3,4-tetrahydro-naphthalene melts upon recrystallization from hexane at142143.

Example 12 The mixture of 5.0 g. 2 [4 (2-phenyl-3,4-dihydro- 1 naphthyl)phenoxy] isobutyric acid, 1.0 g. 10% palladium-charcoal and 200 ml.ethanol is hydrogenated at atmospheric pressure until one mol equivalentof hydrogen is absorbed. Hereupon it is filtered, the filtrateconcentrated to about 25 ml. and upon addition of 5 ml. Water the 2 [4(20c phenyl 1,2,3,4 tetrahydro la naphthyl)-phenoxy] -isobutyric acidcrystallizes and is recrystallized from n-hexane, M.P. 159-161"; it isidentical with the product obtained according to Example 11.

The starting material can be prepared analogous to the proceduredescribed in Example 10 but replacing the phenol used by the equivalentamount of 1 (4 hydroxyphenyl) 2 phenyl 3,4 dihydro-naphthalene which isobtained from the corresponding 1 (4 methoxyphenyl) 2 phenyl 3,4 dihydronaphthalene by the analogous hydrolysis procedure described in Example10 for the tetrahydro-naphthalene derivative.

Example 13 Preparation of 2,000 tablets each containing 0.5 g. of theactive ingredient:

Ingredients: G. Trans-4- [2- 4-chloro-phenyl) 1,2,3 ,4-tetrahydro- 1naphthyl]-phenoxy-acetic acid, g. 1000.0 Sterotex, g 88.0 Alginic acid,g. 42.0 Cellulose acetate phthalate, g. 300.0 Anhydrous ethanol, ml.332.0 Acetone, ml 332.0

Procedure. -The acetic acid derivative, sterotex and alginic acid arepassed through a 20 mesh screen and mixed for 30 minutes. The phthalateis dissolved in the ethanol-acetone mixture and with the solution thepowders are wetted and mixed thoroughly. The granulate is dried withwarm air, passed through a 16 mesh screen and compressed into tabletsusing diameter dies, modified ball punches.

Example 14 Preparation of 1,000 tablets each containing 0.755 g. of theactive ingredient:

Ingredients: G. 2 [4 (2- phenyl 1,2,3,4-tetrahydro-1 naphthyl)-phenoxy]-isobutyric acid 755 0 Microcrystalline cellulose 109.0Polyethylene glycol 6000 powder 18.0 Polyvinyl alcohol powder 18.0

50% aqueous ethanol, q.s.

Procedure-The acid and polyvinyl alcohol are passed through a 20 meshscreen, mixed with the cellulose and the mixture is moistened withethanol. The granulate is dried with warm air, passed through a 12 meshscreen, mixed with the polyethylene glycol and compressed into tabletsusing 1 diameter dies, modified ball punches. In one tablet shown inthis and the foregoing example,

19 the active ingredient may be replaced by 400 mg. of the othercompounds of this invention described in the previous and followingexamples.

Example 15 To the refluxing solution of 6.6 g. 1 (4 hydroxyphenyl) 4phenyl l,2,3,4 tetrahydro-naphthalene in 50 ml. xylene, 0.51 g. sodiumare added in small pieces. After 2 /2 hours reflux 4.5 g. ethyl2-bromo-isobutyrate in 4 ml. xylene are added to the suspension formedand it is refluxed 4 hours more. After cooling 2 ml. methanol are addedto the mixture which is then filtered and the residue washed withmethanol. The filtrate is evaporated in vacuo the residue mixed withwater and the mixture extracted with ethyl acetate. The dried extract isevaporated in vacuo yielding the oily ester. It is dissolved in 50 ml.methanol, to the solution 1.5 g. potassium hydroxide in 25 ml. methanolare added and the mixture is allowed to stand at room temperature overthe weekend. Thereupon it is evaporated under reduced pressure, to theresidue water and diethyl ether are added and the whole is refluxeduntil dissolution occurs. The aqueous layer is acidified withhydrochloric acid, extracted with diethyl ether, the extract washed withwater and concentrated sodium chloride solution, dried and evaporated invacuo. The residue is recrystallized from hexane-diethyl ether andaqueous ethanol to yield the 2 [4-(4-phenyl-1,2,3,4- ten'ahydro lnaphthyl)-phenoxy]-isobutyric acid of the formula melting at 149-151.The starting material is prepared as follows:

The solution of 11.1 g. of l hydroxy 4 phenyll,2,3,4tetrahydro-naphthalene and 4.95 g. phenol in 145 ml. benzene and 48 ml.hexane is added dropwise to a solution of g. phenol and 3.36 g. aluminumchloride while cooling in an ice bath and stirring. Stirring iscontinued for 5 hours at room temperature and for 5 hours at 55-60".Hereupon the cold mixture is poured onto 100 g. ice and 100 ml.concentrated hydrochloric acid and extracted with diethyl ether. Theextract is washed with water until neutral, dried, filtered andevaporated in vacuo. The residue is distilled and the fraction boilingat 195 to 215 /0.15 mm. collected. The so-obtained 1-(4- hydroxy phenyl)4 phenyl 1,2,3,4 tetrahydronaphthalene is recrystallized fromhexane-benzene and melts at 147149.

Example 16 To the stirred and refluxing solution of 10.0 g. 1,8-(4-hydroxy phenyl) 2ot-phenyl-l,2,3,4-tetrahydro-naphthalene (M.P. 67-69")in 100 ml. acetone containing 3.3 g. sodium hydroxide, the solution of4.5 g. chloro-acetic acid in 30 ml. acetone is added dropwise and themixture is refluxed for 7 hours and allowed to stand overnight. Thecrystalline precipitate is filtered off, dissolved in water, thesolution acidified with 2 N hydrochloric acid, extracted with ethylacetate, the extract washed with water, dried and evaporated. Theremaining 4-(2a-phenyl- 201,2,3,4-tetrahydro-lfi-naphthyl)-phenoxy-aeetic acid of the formula Q(I) Q is recrystallized first from hexane, then from benzene-pentane andfinally from aqueous ethanol and melts at 124- 126.

Example 17 which melts after recrystallization from benzene-pentane andaqueous ethanol at l34l35.

Example 18 The mixture of 2.0 g. 1-(4-hydroxy-phenyl)-2-methyl- 2(4-chloro-phenyl)-1,2,3,4-tetrahydro-naphthalene, 0.51 g. sodiumhydroxide and 10 ml. acetone is stirred for 15 minutes, whereupon 0.82g. chloro-acetic acid in 10 ml. acetone are added dropwise. It isrefluxed and stirred for 2 /2 hours, then cooled, diluted with 25 ml.acetone and filtered. The precipitate is dissolved in 25 ml. warm water,the solution acidified with concentrated hydrochloric acid, extractedwith ethyl acetate, the extract washed with Water, dried and evaporated.The so-obtained 4-[2-methyl- 2(4-chloro-phenyl)-1,2,3,4-tetrahydro-l-naphthyl]-phenoxy-acetic acid ofthe formula crystallizes on standing over pentane and melts after 2recrystalhzations from benzene-hexane at l02106.

21 What is claimed is: 1. A member selected from the group consisting ofa compound having the formula in which Ph stands for a member selectedfrom the group consisting of 1,2-phenylene, (lower alkyl)-l,2-phenylene,(lower alkoXy)-1,2-phenylene and (halogeno)-l,2-phenylene, R for amember selected from the group consisting of hydrogen, lower alkyl andhalogeno, alk for alkylene having from one to five carbon atoms, R for amember selected from the group consisting of hydrogen, lower alkyl,N,N-di-lower alkylamino-lower alkyl and N,N- alkyleneimino-lower alkylhaving five to seven ring members and in both of which the nitrogen atomis separated from the oxygen atom by at least two carbon atoms, one of Rand R for hydrogen and the other for a member selected from the groupconsisting of phenyl, (lower alkyl)-phenyl, (lower alkoxy)-phenyl,(halogeno)-phenyl and (R OOC-alk-O)-phenyl wherein R and alk have themeaning given above, and the letter n stands for one of the integers 1and 2, an ammonium or alkali metal salt of a compound in which R ishydrogen and a pharmaceutically acceptable acid addition salt of acompound in which R is N,N-di-lower alkylamino-lower alkyl or N,N-alkyleneimino-lower alkyl.

2. A member selected from the group consisting of a compound having theformula in which R; stands for a member selected from the groupconsisting of hydrogen, lower alkyl, lower alkoxy and halogeno, each ofR and R for a member selected from the group consisting of hydrogen andmethyl, R for a member selected from the group consisting of hydrogenand lower alkyl and R for a member selected from the group consisting ofphenyl and (halogeno)-phenyl, and alkali metal salts of the compounds inwhich R stands for hydrogen.

3. Lower alkyl 2 [4-(2-phenyl-1,2,3,4-tetrahydro-1- naphthyl)-phenoxy]isobutyrate.

4. Ethyl 2 [4 (2-phenyl-1,2,3,4-tetrahydro-l-naphthyl) -phenoxy]-isobutyrate.

5. 2 [4 (Z-phenyl-1,2,3,4-tetrahydro-l-naphthyl)- phenoxy]-isobutyricacid.

6. The alkali metal salts of2-[4-(2-phenyl-1,2,3,4-tetrahydro-l-naphthyl)-phenoxy]-isobutyric acid.

7. Lower alkyl 4-[2-(4-chloro-phenyl)-1,2,3,4-tetrahydrol-naphthyl]-phenoxy-acetate.

8. 4 [2 (4-chloro-phenyl)-l,2,3,4-tetrahydro-l-naphthyIJ-phenoxy-aceticacid.

9. The alkali metal salts of 4-[2-(4-chloro-phenyl)-1,2,3,4-tetrahydro-l-naphthyl]-phenoxy-acetic acid.

10. Lower alkyl2-{4-[2-(4-chloro-phenyl)-1,2,3,4-tetrahydro-l-naphthyl]-phenoxy}-isobutyrate.

11. Ethyl2-{4-[2-(4-chloro-phenyl)-1,2,3,4-tetrahydrol-naphthyl]-phenoxy}-isobutyrate.

12. 2 {4 [2-(4-chloro-phenyl)-l,2,3,4-tetrahydr0-1-naphthyl]-phenoXy}-isobutyric acid.

13. The alkali metal salts of 2-{4-[2-(4-chloro-phenyl)-l,2,3,4-tetrahydro- 1 -naphthyl] -phenoxy}-isobutyric acid 14. Loweralkyl4-(2-phenyl-7-chloro-1,2,3,4-tetrahydro-l-naphthyl)-phenoxy-acetate.

15. 4 (2 phenyl-7-chloro-1,2,3,4-tetrahydro-1-naththyl)-phenoxy-aceticacid.

16. The alkali metal salts of 4-(2-phenyl-7-chlor0-1,2,3,4-tetrahydro-l-naphthyl)-phenoxy-acetic acid.

17. Lower alkyl 4-[2-(4-chloro-phenyl)-1-benzosuberanyl]-phenoxy-acetate.

18. 4 [2 (4-chloro-phenyl)-1-benzosuberanyl]- phenoxy-acetic acid.

19. The alkali metal salts of 4-[2-(4-chloro-phenyl)-1-benzosuberanyl]-phenoxy-acitic acid.

20. Lower alkyl 2-[4-(4-phenyl-l,2,3,4-tetrahydro-1- naphthyl -phenoxy]-isobutyrate.

21. 2 [4 l-phenyl-1,2,3,4-tetrahydro-l-naphthyl)- phenoxy1-isobutyricacid.

22. The alkali metal salts of 2-[4-(4-phenyl-l,2,3,4-tetrahydro-l-naphthyl)-phenoxy]-isobutyric acid.

23. Lower alkyl4-(2-phenyl-l,2,3,4-tetrahydro-1-naphthyl)-phenoxy-acetate.

24. 4 (2 phenyl-l,2,3,4-tetrahydro-1-naphthy1)-phenoXy-acetic acid.

25. The alkali metal salts of4-(2-phenyl-1,2,3,4-tetrahydro-l-naphthyl)-phenoxy-acetic acid.

26. Lower alkyl 4-[2-methyl-2-(4-chloro-phenyl)-1,2,3,4-tetrahydro-1-naphthyl] -phenoXy-acetate.

27. 4 [2methyl-2-(4-chloro-phenyl)-l,2,3,4-tetrahydro-l-naphthyl]-phenoxy-aceticacid.

28. The alkali metal salts of 4-[2-methyl-2-(4-chlorophenyl) 1,2,3,4tetrahydro-l-naphthyl]-phenoxy-acetic acid.

References Cited UNITED STATES PATENTS 3,320,271 5/1967 Lednicer.

2,198,293 4/1940 Reiif et al. 260520 X LORRAINE A. WEINBERGER, PrimaryExaminer D. STENZEL, Assistant Examiner US. Cl. X.R.

